EP0853618A1 - Substituierte ((sulfinsäure, sulfonsäure, sulfonylamino oder sulfinylamino)n-(aminoimonomethyl)phenylalkyl)-azaheterocyclylamid-derivate - Google Patents

Substituierte ((sulfinsäure, sulfonsäure, sulfonylamino oder sulfinylamino)n-(aminoimonomethyl)phenylalkyl)-azaheterocyclylamid-derivate

Info

Publication number
EP0853618A1
EP0853618A1 EP96919298A EP96919298A EP0853618A1 EP 0853618 A1 EP0853618 A1 EP 0853618A1 EP 96919298 A EP96919298 A EP 96919298A EP 96919298 A EP96919298 A EP 96919298A EP 0853618 A1 EP0853618 A1 EP 0853618A1
Authority
EP
European Patent Office
Prior art keywords
oxopyrrolidin
trifluoroacetate
benzyl
aminoiminomethyl
sulfonic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP96919298A
Other languages
English (en)
French (fr)
Other versions
EP0853618B1 (de
EP0853618A4 (de
Inventor
William R. Ewing
Michael R. Becker
Henry W. Pauls
Daniel L. Cheney
Jonathan Stephen Mason
Alfred P. Spada
Yong Mi Choi-Sledeski
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharmaceuticals Inc
Original Assignee
Rhone Poulenc Rorer Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rhone Poulenc Rorer Pharmaceuticals Inc filed Critical Rhone Poulenc Rorer Pharmaceuticals Inc
Publication of EP0853618A1 publication Critical patent/EP0853618A1/de
Publication of EP0853618A4 publication Critical patent/EP0853618A4/de
Application granted granted Critical
Publication of EP0853618B1 publication Critical patent/EP0853618B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/12—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the compounds of formula I exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More especially, they are Factor Xa inhibitors.
  • the present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use, which are for treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of Factor Xa.
  • Factor Xa is the penultimate enzyme in the coagulation cascade. Both free factor Xa and factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) are inhibited by compounds of formula I.
  • Factor Xa inhibition is obtained by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma co- factor antithrombin III. Effective factor Xa inhibition is achieved by
  • administering the compounds either by oral administration, continuous intravenous infusion, bolus intravenous administration or any other parenteral such that it achieves the desired effect of preventing the factor Xa induced formation of thrombin from prothrombin.
  • Anticoagulant therapy is indicated for the treatment and prophylaxis of a variety of thrombotic conditions of both the venous and arterial vasculature.
  • abnormal thrombus formation is primarily associated with arteries of the coronary, cerebral and peripheral vasculature.
  • the diseases associated with thrombotic occlusion of these vessels principally include acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication and bypass grafting of the coronary (CABG) or peripheral arteries.
  • AMI acute myocardial infarction
  • PTCA percutaneous transluminal coronary angioplasty
  • CABG bypass grafting of the coronary
  • Chronic anticoagulant therapy may also be beneficial in preventing the vessel luminal narrowing (restenosis) that often occurs following PTCA and CABG, and in the maintenance of vascular access patency in long-term hemodialysis patients.
  • restenosis vessel luminal narrowing
  • CABG vessel luminal narrowing
  • DVT deep vein thrombosis
  • DVT further predisposes the patient to a higher risk of pulmonary thromboembolism.
  • a systemic, disseminated intravascular coagulopathy (DIC) commonly occurs in both vascular systems during septic shock, certain viral infections and cancer.
  • This invention is directed to the pharmaceutical use of a compound of formula I below for treating a patient suffering from a physiological disorder capable of being modulated by inhibiting an activity of Factor Xa, where formula I is as follows: is phenyl or monocyclic heteroaryl; R is hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl or hydroxyalkyl;
  • R 1 is hydrogen, R 3 S(O) p - or R 3 R 4 NS(O) p -;
  • R 3 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl or optionally substituted heteroaralkenyl, or R and R 3 taken together form a 5 to 7 membered ring; and R 4 is optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or R 3 and R 4 taken together with the nitrogen to which R 3 and R 4 are attached form an optionally substituted 4 to 7 membered heterocyclyl;
  • X 1 and X 1' are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl or hydroxyalkyl, or X 1 and X 1' taken together form oxo;
  • X 2 and X 2 are hydrogen, or taken together form oxo;
  • X 3 is hydrogen, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or X 3 and one of X 1 and X 1' taken together form a
  • X 4 is hydrogen, optionally substituted alkyl, optionally substituted aralkyl, or hydroxyalkyl;
  • R 5 is hydrogen, R 6 O 2 C-, R 6 O-, cyano, R 6 CO-, optionally substituted lower alkyl, nitro or Y 1' Y 2' N-;
  • Y 1' and Y 2' are independently hydrogen, alkyl, aralkyl or heteroaralkyl;
  • X 6 and X 6 are independently hydrogen, R 7 R 8 N-, R 9 O-, R 7 R 8 NCO-, R 7 R 8 NSO 2 -, R 9 CO-, halo, cyano or nitro;
  • R 6 is hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl or optionally substituted heteroaralkyl;
  • R 7 and R 8 are independently hydrogen or optionally substituted lower alkyl, or one of R 7 and R 8 is hydrogen and the other of R 7 and R 8 is R 10 (O)CCH 2 - or lower acyl;
  • R 9 is hydrogen, optionally substituted lower alkyl, lower acyl or R 10 (O)CCH 2 -;
  • R 10 is hydrogen, optionally substituted lower alkyl, alkoxy or hydroxy; m is 0, 1 , 2 or 3; n is 1 , 2 or 3; or p is 1 or 2, a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. “Lower alkyl” means about 1 to about 4 carbon atoms in the chain which may be straight or branched.
  • the alkyl may be substituted with one or more "alkyl group substituents" which may be the same or different, and include halo, cycloalkyl, alkoxy, amino, acylamino, aroylamino, carboxy, alkoxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl or Y 1' Y 2' NCO-, where Y 1' and Y 2' are independently hydrogen, alkyl, aralkyl or heteroaralkyl.
  • alkyl group substituents may be the same or different, and include halo, cycloalkyl, alkoxy, amino, acylamino, aroylamino, carboxy, alkoxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl or Y 1' Y 2' NCO-, where Y 1' and Y 2' are independently hydrogen, alkyl, aralkyl or heteroaralkyl.
  • Exemplary alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, Apropyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, pyridylmethyloxycarbonylmethyl.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms.
  • Exemplary monocyclic cycloalkyl rings include cyclopentyl, fluorocyclopentyl, cyclohexyl and cycloheptyl.
  • Exemplary multicyclic cycloalkyl rings include 1-decalin, adamant-(1- or 2-)yl and norbornyl.
  • Heterocyclyl means a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 ring atoms. Preferred rings include about 5 to about 6 ring atoms wherein one of the ring atoms is oxygen, nitrogen or sulfur.
  • the heterocyclyl is optionally partially unsaturated or optionally substituted by one or more alkyl, halo, aryl, heteroaryl, fused aryl or fused heteroaryl.
  • Exemplary monocyclic rings include pyrrolidyl, piperidyl, tetrahydrofuranyl, tetrahydrothienyl and tetrahydrothiopyranyl.
  • the thio or nitrogen moiety of the heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S- oxide or S,S-dioxide.
  • Aryl means aromatic carbocyclic radical containing about 6 to about 10 carbon atoms.
  • exemplary aryl include phenyl or naphthyl, or phenyl
  • aryl group substituent includes hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,
  • heteroaralkylthio fused cycloalkyl, fused heterocyclyl, arylazo, heteroarylazo, Y 1 Y 2 N-, Y 1 Y 2 NCO- or Y 1 Y 2 NSO 2 -, where Y 1 and Y 2 are independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, or Y 1 , Y 2 and N taken together form a heterocyclyl.
  • the aryl group substituents are as defined herein. Preferred aryl groups are optionally substituted phenyl or optionally substituted naphthyl.
  • Preferred aryl group substituents include hydrogen, alkyl, hydroxy, acyl, aryl aroyl, aryloxy, halo, nitro, alkoxy, cyano, alkoxycarbonyl, acylamino, alkylthio, Y 1 Y 2 N-, Y 1 Y 2 NCO- or Y 1' Y 2' NSO 2 -, where Y 1' and Y 2' are independently hydrogen, alkyl, aralkyl or heteroaralkyl; preferred phenyl group substituents are aryloxy and aryl; and preferred naphthyl group substituents are nitro, alkoxy and amino.
  • Heteroaryl means about a 5- to about a 10- membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the carbon atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • the “heteroaryl” may also be substituted by one or more of the above-mentioned “aryl group substituents”.
  • heteroaryl groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimiddazolyl, benzothienyl, quinolinyl, imidazolyl and isoquinolinyl.
  • Preferred heteroaryl groups in the R substituent include benzothienyl, thienyl, imidazolyl, pyridyl
  • heteroaryl examples include thienyl, pyridyl and furanyl.
  • Alkyl means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls contain a lower alkyl moiety.
  • Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
  • Heteroaralkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl moiety. Exemplary heteroaralkyl groups may contain thienyl, pyridyl, imidazolyl and pyrazinyl.
  • Alkenyl means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl moiety. An exemplary aralkenyl group is 2-phenethenyl.
  • Heteroaralkenyl means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl moiety. Exemplary heteroaralkenyl groups may contain thienyl, pyridyl, imidazolyl and pyrazinyl.
  • Hydroalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Exemplary hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
  • acyl means an H-CO- or alkyl-CO- group in which the alkyl group is as previously described. Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
  • Aroyl means an aryl-CO- group in which the alkyl group is as previously described.
  • exemplary groups include benzoyl and 1- and 2- naphthoyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
  • Aryloxy means an aryl-O- group in which the aryl group is as
  • aryloxy groups include phenoxy and naphthoxy.
  • Alkyloxy means an aralkyl-O- group in which the aralkyl groups is as previously described.
  • exemplary aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • Exemplary alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio.
  • Arylthio means an aryl-S- group in which the aryl group is as
  • arylthio groups include phenylthio and naphthylthio.
  • Alkylthio means an aralkyl-S- group in which the aralkyl group is as previously described.
  • An exemplary aralkylthio group is benzylthio.
  • Y 3 Y 4 N- means a substituted or unsubstituted amino group, wherein Y 3 and Y 4 are as previously described.
  • exemplary groups include amino (H 2 N-), methylamino, ethylmethylamino, dimethylamino and diethylamino.
  • Alkoxycarbonyl means an alkyl-O-CO- group.
  • alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
  • Aryloxycarbonyl means an aryl-O-CO- group.
  • aryloxycarbonyl groups include phenoxy- and naphthoxycarbonyl.
  • Alkoxycarbonyl means an aralkyl-O-CO- group.
  • An exemplary aralkoxycarbonyl group is benzyloxycarbo nyl.
  • Y 3 Y 4 NCO- means a substituted or unsubstituted carbamoyl group, wherein Y 3 and Y 4 are as previously described.
  • Exemplary groups are carbamoyl (H 2 NCO-) and dimethylaminocarbamoyl (Me 2 NCO-).
  • Y 3 Y 4 NSO 2 - means a substituted or unsubstituted sulfamoyl group, wherein Y 3 and Y 4 are as previously described.
  • exemplary groups are aminosulfamoyl (H 2 NSO 2 -) and dimethylaminosulfamoyl (Me 2 NSO 2 -).
  • Acylamino is an acyl-NH- group wherein acyl is as defined herein.
  • Aroylamino is an aroyl-NH- group wherein aroyl is as defined herein.
  • Alkylsulfonyl means an alkyl-SO 2 - group. Preferred groups are those in which the alkyl group is lower alkyl.
  • Alkylsulfinyl means an alkyl-SO- group. Preferred groups are those in which the alkyl group is lower alkyl.
  • Arylsulfonyl means an aryl-SO 2 - group.
  • Arylsulfinyl means an aryl-SO- group.
  • Halo means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo, and more preferred are fluoro or chloro.
  • a preferred embodiment of the invention is a method for treating a patient suffering from a physiological disorder capable of being modulated by inhibiting an activity of Factor Xa by administering a therapeutically effective amount of a compound of formula I.
  • a preferred compound aspect of the invention is the compound of formula I wherein R 3 is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted thienyl or optionally substituted benzothienyl.
  • Another preferred compound aspect of the invention is the compound of formula I wherein n is 1 , and m is 1.
  • Another preferred compound aspect of the invention is the compound of formula I wherein X 2 and X 2 , taken together are oxo.
  • Another preferred compound aspect of the invention is the compound of formula I wherein X 1 , X 1 , X 3 and X 4 are hydrogen.
  • Another preferred compound aspect of the invention is the compound of
  • R is hydrogen, methyl, aralkyl, heteroaralkyl, HO 2 CCH 2 -, HOC(O)CH 2 -, H 2 NC(O)CH 2 -, (aralkyl)HNC(O)CH 2 - or
  • Another preferred compound aspect of the invention is the compound of formula I wherein X 1 is hydrogen and X 1 , is carboxyalkyl, alkoxycarbonylalkyl or aryl, or X 1 and X 1 , taken together form oxo.
  • Another preferred compound aspect of the invention is the compound of formula I wherein R 1 is R 3 SO 2 -..
  • Another preferred compound aspect of the invention is the compound of formula I wherein R 1 is R 3 R 4 NSO 2 -.
  • Another preferred compound aspect of the invention is the compound of claim 1 wherein one of X 6 and X 6 , is amino in a para position relative to the Species according to the invention are selected from the group consisting of:
  • Naphthalene-2-sulfonic acid ⁇ 1-[3-(aminoiminomethyl)benzyl]-2-oxopyrrolidin- 3-(S)-yl ⁇ methyl amide trifluoroacetate
  • Naphthaiene-2-sulfonic acid ⁇ 1-[3-(aminoiminomethyl)benzyl]pyrrolidin-3-(S)- yl ⁇ amide bistrifluoroacetate
  • Naphthalene-2-sulfonic acid ⁇ 1-[3-(aminoiminomethyl)benzyl]-2-oxopiperidin- 3-yl ⁇ amide trifluoroacetate
  • 7-Methoxynaphthalene-2-sulfonic acid ⁇ 1-[3-(aminoiminomethyl)benzyl]-2-oxo- azepan-3-(S)-yl ⁇ amide trifluoroacetate
  • N-Methylpyrid-4-ylphenyl-4-sulfonic acid ⁇ 1-[3-(aminoiminomethyl)benzyl]-2- oxopyrrolidin-3(S)-yl ⁇ amide trifluoroacetate
  • 2-Methoxyquinoline-7-sulfonic acid ⁇ 1-[3-(aminoiminomethyl)benzyl]-2- oxopyrrolidin-3-(S)-yl ⁇ amide trifluoroacetate
  • 2-Methoxyquinoline-7-sulfonic acid ⁇ 1-[3-(aminoiminomethyl)benzyl]-2- oxopyrrolidin-3-(S)-yl ⁇ amide trifluoroacetate
  • 6-Methoxynaphthalene-2-sulfonic acid ⁇ 1-[3-(hydroxyaminoiminomethyl)- benzyl]-2-oxopyrrolidin-3-(S)-yl ⁇ -methylamide trifluoroacetate; 4-Amino-3-[3-(S)-(7-methoxynaphthalene-2-sulfonylamino)-2-oxopyrrolidin-1- yl-methyl]benzamidine dihydrochloride;
  • Ar 1 , R, R 1 , R 2 , X 3 , X 4 , X 5 , X 5 , X 6 , X 6' , m and n are as defined above, and X 1 and X 1 , are hydrogen and X 2 and X 2' , taken together are oxo, may be prepared by reacting a compound of formula II
  • X 3 , X 4 and m are as defined above, and P 1 is alkyl, aralkyl, or aryl, and P 2 is (alkyl, aralkyl, or aryl)carbamate, by reductive amination using a cyano(phenyl or heteroaryl)alkylamine of formula III
  • Ar 1 , X 6 , X 6 , and n are as defined above, in an alcoholic solvent such as methanol and an imine reducing reagent such as sodium cyanoborohydride, sodium triacetoxyborohydride or catalytic hydrogenation using for example palladium at a temperature from about 0°C to about 100°C to give the cyclic structure represented by formula IV.
  • Ar 1 , X 3 , X 4 , X 6 , X 6' , m and n are as defined above, and X 1 and X 1 , are hydrogen, X 2 and X 2' , taken together are oxo, and P 2 is (alkyl, aralkyl, or aryl)carbamate.
  • the P 2 group is then removed by the appropriate deblocking procedures known for carbamates such as strong acid, strong base or catalytic hydrogenation to give compounds of formula V.
  • Halo is a halogen atom such as chloro
  • a base such as a trialkylamine
  • an inert solvent such as dichloromethane, tetrahydrofuran, ether or acetonitrile
  • DMAP dimethyl aminopyridine
  • compounds of formula VII can be dissolved in a solution of pyridine containing a tertiary amine base such as triethyl amine saturated with hydrogen sulfide at a temperature from about 0°C to about 60°C.
  • a tertiary amine base such as triethyl amine saturated with hydrogen sulfide at a temperature from about 0°C to about 60°C.
  • the resulting product is then dissolved in an organic solvent such as acetone and reacted with an alkyl halide such as methyl iodide at a temperature 0°C to about 80°C.
  • compounds of formula I may be prepared starting with may be prepared by reacting a compound of formula VIII wherein X 3 , X 4 and m are as defined above, X 2 , is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonylalkyl or hydroxyalkyl, and P 1 is alkyl, aralkyl, or aryl, and P 2 is (alkyl, aralkyl, or aryl)carbamate, with a compound of formula III as defined above in an analogous fashion to the
  • That compound of formula IV may then be converted to a compound of formula V and then on to compounds of formulae Vila and Vllb wherein Ar 1 , R 3 , R 4 , X 3 , X 4 , X 6 , X 6' , m, n and p are as defined above, and X 1 and X 1 , are oxo, and one X 2 and X 2 ., is hydrogen and the other of X 2 and X 2 , is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or hydroxyalkyl in an
  • compounds of formula V and formula IV may be converted to a compounds of formula I as follows.
  • Compounds of formulae IV or V are treated with an alcoholic solvent such as ethanol saturated with HCl.
  • the resulting product is then treated with an alcoholic solvent such as methanol saturated with ammonia to give respectively a compound of formula IX or X wherein Ar 1 , X 1 , X 1' , X 2 , X 2' , X 3 , X 4 , X 6 , X 6' , P 2 , m and n are as defined above.
  • a compound of formula IX may then be converted to a compound of formula X by an appropriate deblocking procedure described above.
  • a compound of formula X may then be dissolved in an organic solvent such as ethanol or dimethylformamide and compounds of formulae Via or Vlb are added at a temperature from about 0°C to about 100°C in the presence or absence of an activating reagent such as DMAP with a sulfonylchloride to give compounds represented by formula I.
  • an organic solvent such as ethanol or dimethylformamide
  • compounds of formulae Via or Vlb are added at a temperature from about 0°C to about 100°C in the presence or absence of an activating reagent such as DMAP with a sulfonylchloride to give compounds represented by formula I.
  • a compound of formula I may be prepared starting with a compound of formula XI.
  • X 1 , X 1' , X X 2' , X 3 , X 4 , X 6 , X 6' , m and P 2 are as defined above.
  • a compound of formula XI is dissolved in an inert organic solvent such as tetrahydrofuran at a temperature from about -78°C to about 25°C. To that solution is added a strong base such as sodium hydride, lithium
  • a compound of formula I in which R is other than hydrogen may be prepared starting with compounds of formulae Vlla or Vllb.
  • Compounds of formulae Vlla or Vllb may be dissolved in an inert organic solvent such as tetrahydrofuran, dioxane, or dimethyl formamide at a temperature of about 0°C to about 100°C.
  • an inert organic solvent such as tetrahydrofuran, dioxane, or dimethyl formamide
  • R 1 , X 1 , X 1' , X X 2' , X 3 , X 4 , X 6 , X 6 ' , m and n are as defined above, and R is optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl or hydroxyalkyl.
  • a compound of formula XIV may be treated with an alcoholic solvent such as ethanol saturated with HCl.
  • R 2 and R 5 are independently hydrogen or alkyl, or when one of R 2 or R 5 is hydrogen, then the of R 2 or R 5 may be alkoxy or amino.
  • amidine species is treated with an alkyl chloroformate in an appropriate solvent such as methylene chloride or dimethyl formamide in the presence of a base such as a trialkylamine to give a compound of formula I wherein R 5 is R 6 O 2 C.
  • an acylating species such as an acyl chloride in the presence of a base such as
  • trialkylamine to give compounds of formula I wherein R 5 is R 6 OC.
  • compounds wherein R 5 is cyano may be prepared by treatment of the amidine with cyanogen bromide and a trialkyl amine in an appropriate an alcoholic solvent.
  • a compound of formula I wherein X 5 and X 5 , are hydrogen may be prepared by reduction of compounds of formulae VIla, Vllb or XIV using hydrogenation in an appropriate solvent such as methanol in the presence of a catalyst such as rhodium on alumina. This transformation may also be achieved using a hydride reagent such as diisobutyl aluminum hydride to give a compound of formula I wherein X 5 and X 5 , are hydrogen.
  • the compounds of the present invention are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention.
  • acid addition salts are formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form.
  • the acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on the activity of Factor Xa inherent in the free base are not vitiated by side effects ascribable to the anions.
  • Pharmaceutically acceptable salts within the scope of the invention are those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, maionic acid, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like.
  • the corresponding acid addition salts comprise the following: hydrohalides, e.g.
  • hydrochloride and hydrobromide sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate, oxaiate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-B-hydroxynaphthoates, gentisates, mesylates, isethionates and di-p-toluoyltartratesmethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.
  • acid addition salts of the compounds of this invention are prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods.
  • the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • the compounds of this invention may be regenerated from the acid addition salts by the application or adaptation of known methods.
  • parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • an alkali e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form.
  • the bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are nontoxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on the activity of Factor Xa inherent in the free acid are not vitiated by side effects ascribable to the cations.
  • salts including for example alkali and alkaline earth metal salts, within the scope of the invention are those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, omithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine,
  • Metal salts of compounds of the present invention may be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous or organic solvent with the free acid form of the compound.
  • the aqueous solvent employed may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate.
  • Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating.
  • Amine salts of compounds of the present invention may be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound.
  • Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone. Amino acid salts may be similarly prepared.
  • the base addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods.
  • parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
  • Salt forms according to invention also include compounds having a quarternarized nitrogen.
  • the quarternarized salts are formed by methods such as by alkylation of a sp 3 or sp 2 hybridized nitrogen in the compounds.
  • salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
  • Compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in either the R or S
  • Geometrical isomers include the cis and trans forms of compounds of the invention having alkenyl or diazenyl (azo) moieties.
  • the present invention comprises the individual geometrical isomers and stereoisomers and mixtures thereof. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the
  • Boc-L-Asp-OBn (15 g, 46.4 mmol) is dissolved in 50 mL of THF and cooled to -10°C.
  • the solution is treated with N-methylmorpholine (4.9 g, 48.7 mmol) and stirred for 5 minutes.
  • To the solution is added dropwise isobutyl chloroformate (6.3 g, 46.4 mmol). After the addition is completed, the solution is stirred for 1 minute, then filtered through a pad of Celite. The collected solution is cooled to -10°C.
  • sodium borohydride (2.63 g, 70 mmol) predissolved in 50 mL of water. The solution is stirred for 2 minutes.
  • the solution is poured into a separatory funnel and diluted with 800 mL of EtOAc.
  • the organic layer is washed with water and saturated NaCl.
  • the organic layer is dried over MgSO 4 , filtered and concentrated.
  • the resulting residue is added to a solution of oxalyl chloride (30 mL of a 2 M solution in CH 2 CI 2 , 60 mmol), and methyl sulfoxide (7.25 g, 92.8 mmol) in 250 mL of CH 2 CI 2 at -78°C.
  • the reaction mixture is stirred at -78°C for 40 minutes, then triethylamine (14 g, 140 mmol) is added.
  • the reaction mixture is stirred at -78°C for 1 hour and then is stirred at room temperature for 30 minutes.
  • the solution is poured into 200 mL of a 20% citric acid/water solution.
  • the resulting mixture is poured into a separatory funnel and the layers are separated.
  • the organic layer is washed with water and saturated NaCl.
  • the organic layer is dried over MgSO 4 , filtered and concentrated.
  • the residue is purified by column chromatography eluting with a gradient of 10% EtOAc/hexanes to 30% EtOAc/hexanes.
  • the product aldehyde (12 g, 39 mmol) is obtained as an oil.
  • Naphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.46 g, 1.13 mmol) is dissolved in 50 mL of ethanol. The solution is cooled to 0°C and HCl gas is bubbled through the solution for 10 minutes. The ice bath is removed and the reaction mixture is stirred at room temperature for 6 hours. After this time, the solution is concentrated. The residue is dissolved in 50 mL of methanol. The solution is cooled to 0°C and ammonia gas is bubbled through the solution for 10 minutes. The reaction mixture is stirred for 24 hours. After this time, the solution is concentrated. The residue is purified by RP- HPLC eluting with a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60%
  • the title compound is prepared from 3-(3-amino-5-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 1 , Part D using 2- dibenzofuransulfonyl chloride in place of 2-naphthalene sulfonyi chloride.
  • the crude product is purified by column chromatography in a gradient of CH 2 CI 2 to 5% MeOH/CH 2 CI 2 .
  • the resulting mixture is heated at reflux for 3.5 hours, allowed to cool to room temperature and concentrated in vacuo to provide the crude amidine salt.
  • the crude product is purified by RP- HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1 % TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound (0.21 g, 0.36 mmol) as a white solid.
  • Triethylamine (0.4 g, 4 mmol) is added and the mixture is stirred for 16 hours.
  • the reaction mixture is diluted with EtOAc and washed with 1 N HCl, 10% Na 2 CO 3 and saturated NaCl.
  • the residue is purified by column chromatography eluting with a gradient of 10% EtOAc/CH 2 CI 2 to 15% EtOAc/CH 2 CI 2 to give the title compound (0.15 g , 0.36 mmol) as a solid.
  • 3-Bromoanisole (3.5 g, 18.7 mmol) is dissolved in 40 mL of THF and cooled to -78°C. To the solution is added dropwise a 2.5 M solution of n-butyllithium in hexanes (7.5 mL, 18.7 mmol). After 10 minutes, a solution of zinc chloride (20 mL, 19.6 mmol) in ether is added and the cooling bath is removed. The reaction mixture is stirred at room temperature for 2 hours. After this time, a solution of 4-iodobromobenzene (5.6 g, 19.6 mmol) and Pd(Ph 3 P) 4 (1.1 g, 1 mmol) in 10 mL of THF is added to the reaction flask.
  • 3'-Methoxy-biphenyl-4-bromide (1.5 g, 5.7 mmol) is dissolved in 20 mL of THF and cooled to -78°C. To the solution is added a 2.5 M solution of
  • biarylsulfinate as a solid.
  • the solid is suspended in 15 mL of hexanes and cooled to 0°C.
  • a 1 M solution of sulfuryl chloride (4.2 mL, 4.2 mmol) in CH 2 CI 2 .
  • the resulting solution is concentrated.
  • the residue is triturated with hexanes to give the title compound (0.6 g, 2.25 mmol) as a solid.
  • the mixture is diluted with water and extracted with CHCl 3 (2x100 mL).
  • the combined organic layers are washed successively with water, saturated NaHCO 3 solution and saturated NaCl.
  • the organic phase is dried over anhydrous MgSO 4 , filtered and concentrated to give 10 g of a crude oil.
  • the crude product is purified by column chromatography in a gradient of 5% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (3.8 g, 14.8 mmol) as a white crystalline solid.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 1, Part D using 7- methoxynaphthalene-2-sulfonyl chloride.
  • the crude product is triturated from 50% EtOAc/hexanes solution to give the title compound as a beige solid.
  • 7-Methoxynaphthalene-2-sulfonic acid ⁇ 1-[3-(aminoiminomethyl)benzyl]-2- oxopyrrolidin-3-(R)-yl ⁇ amide trifluoroacetate is prepared from 7- methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-(3R)- yl]amide as above.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 1, Part D using 7- ethoxynaphthalene-2-sulfonyl chloride.
  • the crude product is triturated from 50% EtOAc/hexanes solution to give the title compound as a beige solid.
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • the title compound is prepared from 6-hydroxynaphthalene-2-sulfonic acid, sodium salt as in EXAMPLE 9, Part A.
  • the crude product mixture is purified by column chromatography in a gradient of 5% EtOAc/hexanes to 10%
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 1 , Part D using 5-chloro-6- methoxynaphthalene-2-sulfonyl chloride. The crude product is triturated from
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • the title compound is prepared from 6,7-dihydroxynaphthalene-2-sulfonic acid, sodium salt hemihydrate as in EXAMPLE 9, Part A.
  • the crude product mixture is purified by column chromatography in a gradient of 5% EtOAc/hexanes to 30% EtOAc/hexanes to give the title compound as a minor by-product.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 1 , Part P using 5-chloro- 6,7-dimethoxynaphthalene-2-sulfonyl chloride. The crude product is triturated from EtOAc to give the title compound as a beige solid.
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 1 , Part D using 2- dibenzofuransulfonyl chloride. The crude product is triturated from EtOAc to give the title compound as a beige solid.
  • Dibenzofuran-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)- yl]amide is dissolved in 10 mL of a 2:1 mixture of EtOH/CH 2 CI 2 and converted to the title compound as in EXAMPLE 1 , Part E.
  • the imidate intermediate is formed over a period of 24 hours at room temperature.
  • the amidine formation occurred over a period of 40 hours at room temperature.
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 1, Part P using N-Cbz-7- aminonaphthalene-2-sulfonyl chloride in place of 7-methoxynaphthalene-2- sulfonyl chloride.
  • the crude product is purified by column chromatography using a gradient of 10% EtOAc/CH 2 CI 2 to 25% EtOAc/CH 2 CI 2 to give the title compound as a solid.
  • N-Cbz-7-aminonaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2- oxopyrrolidin-3-(S)-yl]amide is dissolved in 10 mL of a 2:1 mixture of
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • the title compound is prepared from 4-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 1 , Part D.
  • the crude product is triturated from EtOAc to give the title compound as a white solid.
  • 1 H NMR (PMSO-d 6 , 300 MHz) ⁇ 8.50 (s, 1 H), 8.00 (m, 2H), 7.93 (m, 3H), 7.65 (m, 5H), 7.28 (m, 1 H), 4.45 (AB, 2H), 3.80 (m, 1H), 3.20 (m, 2H), 2.55 (m, 1 H), 2.11 (m, 1 H).
  • D. Naphthalene-2-sulfonic acid ⁇ 1-[4-(aminoiminomethyl)benzyl]-2- oxopyrrolidin-3-(S)-yl ⁇ amide trifluoroacetate.
  • Naphthalene-2-sulfonic acid [1-(4-cyanobenzyl)-2-oxppyrrolidin-3-(S)-yl]amide is dissolved in 10 mL of a 2:1 mixture of EtOH/CH 2 CI 2 and converted to the title compound as in EXAMPLE 1 , Part E.
  • the imidate intermediate is formed over a period of 18 hours at room temperature.
  • the amidine formation occurred over a period of 48 hours at room temperature.
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • Naphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.3 g, 0.74 mmol) is dissolved in 9 mL of an 8:1 mixture of THF/PMF and cooled to 0°C.
  • Sodium hydride (30 mg of a 60% dispersion in mineral oil, 0.75 mmol) is added and the solution is stirred for 15 minutes.
  • methyl iodide (0.33 g, 2.34 mmol). The cooling bath is removed and the solution is stirred at room temperature for 2 hours.
  • the solution is poured into a separatory funnel and diluted with 100 mL of EtOAc.
  • Naphthalene-2-sulfonic acid ⁇ 1-[3-(aminoiminomethyl)benzyl]-pyrrolidin-3-(S)- yl ⁇ amide bistrifluoroacetate.
  • N-Boc-3-aminopyrrolidine (1.09 g, 5.83 mmol) is dissolved in 30 mL of CH 2 CI 2 .
  • To the solution is added triethylamine (0.61 g, 6.02 mmol) followed by 2- naphthalene sulfonyl chloride (1.32 g, 5.83 mmol).
  • the reaction mixture is stirred for 4 hours.
  • the crude mixture is diluted with 150 mL of EtOAc and washed with 1 N HCl, 10% Na 2 CO 3 and saturated NaCl.
  • the organic layer is dried over MgSO 4 , filtered and concentrated to give the title compound (2.19 g, 5.8 mmol) as an oil.
  • Naphthalene-2-sulfonic acid-N-Boc-3-(S)-aminopyrrolidine (1.8 g, 4.78 mmol) is dissolved in 50 mL of CH 2 CI 2 . Trifluoroacetic acid (8 mL) is added dropwise. The reaction mixture is stirred for 16 hours. The solution is concentrated in vacuo and then reconcentrated from toluene to give the title compound (1.8 g, 4.64 mmol).
  • Naphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-pyrrolidin-3-(S)-yl]amide.
  • Naphthalene-2-sulfonic acid-pyrrolidin-3-(S)-ylamide trifluoroacetate (0.52 g,
  • Boc-Asp-OBn (3.23 g, 10 mmol) is dissolved in 100 mL of THF. Triethylamine (2.53 g, 25 mmol) is added followed by m-cyanobenzylamine hydrochloride (1.75 g, 10.4 mmol). The reaction mixture is cooled to -10°C, and the BOP reagent (4.42 g, 10 mmol) is added. The mixture is stirred for
  • N-Boc-Asp-(m-cyanobenzylamine)-OBn (1 g, 2.08 mmol) is dissolved in 20 mL of THF and cooled to -78°C.
  • a 1 M solution of lithium hexamethyldisilylazide (4.8 mL, 4.8 mmol) in THF is added dropwise.
  • the mixture is stirred for 20 minutes and 20 mL of saturated NH 4 CI is added.
  • the solution is extracted with EtOAc and then washed with 1 N HCl, 10% Na 2 CO 3 and saturated NaCl.
  • the organic layer is dried over MgSO 4 , filtered and concentrated.
  • the residue is purified by column chromatography eluting with 20% EtOAc/CH 2 CI 2 to give the title compound (0.65 g, 1.8 mmol) as a solid.
  • the title compound is prepared as in EXAMPLE 1, Part E using naphthalene-2- sulfonic acid [1-(3-cyanobenzyl)-2-oxopiperidin-3-yl]amide as the starting material.
  • the title compound is prepared as in EXAMPLE 1, Part D using 3-(3-(S)- amino-2-oxoazepan-1-ylmethyl)benzonitrile hydrochloride and 7-methoxynaphthalene sulfonyl chloride as the starting materials.
  • the title compound is prepared as in EXAMPLE 1, Part E using 7-methoxy naphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxoazepan-3-(S)-yl]amide as the starting material.
  • the title compound is prepared as in EXAMPLE 17, Part A using 7- methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)- yl]amide as the starting material.
  • reaction mixture is stirred at 0°C for 0.5 hours and then is allowed to warm to ambient temperatures. After 3 hours, the reaction mixture is quenched by the addition of saturated NH 4 CI and diluted with EtOAc. The layers are separated. The organic layer is washed with 1 N HCl, H 2 O and saturated NaCl. The organic layer is dried over MgSO 4 , filtered, and
  • 6-Methoxynaphthalene-2-sulfonic acid [1 -(3-cyanobenzyl)-2-oxopyrrolidin-3- (S)-yl]amide (0.18 g, 0.41 mmol) is dissolved in 10 mL of a 2:1 mixture of EtOH/CH 2 CI 2 . The solution is cooled to 0°C and HCl gas is bubbled through the solution for 10 minutes. The ice bath is removed and the reaction mixture is stirred at room temperature for 18 hours. After this time, the soluiton is concentrated and pumped under high vacuum until dry. The residue is dissolved in 10 mL of methanol, cooled to 0°C and ammonia gas is bubbled through the solution for 10 minutes.
  • the reaction mixture is stirred at room temperature for 42 hours. After this time, the solution is concentrated and the residue is purified by RP-HPLC eluting with a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) over a 30 min period. The appropriate fractions are lyophilized to give the title compound (0.11 g, 0.19 mmol) as an amorphous white solid.
  • 6-Methoxynaphthalene-2-sulfonic acid ⁇ 1-[3-(aminoiminomethyl)benzyl]-2- oxopyrrolidin-3-(S)-yl ⁇ methyl amide trifluoroacetate.
  • the title compound is prepared as described in EXAMPLE 24, Part C using 6- methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)- yl]methyl amide as the starting material.
  • the imidate intermediate is formed over a period of 18 hours at room temperature.
  • the amidine formation occurred over a period of 18 hours at room temperature.
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/ H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fiactions are lyophilized to provide the title compound as a white solid.
  • the amidine formation occurred over a period of 18 hours at room temperature.
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • the title compound is prepared as described in EXAMPLE 24, Part A using 7-hydroxynaphthalene-2-sulfonic acid, sodium salt (15 g, 60.9 mmol) in place of 6-hydroxynaphthalene-2-sulfonic acid, sodium salt.
  • the crude 7- methoxynaphthalene-2-sulfonic acid, sodium salt (12.6 g) obtained is likewise chlorinated in the presence of excess phosphorous oxychloride and
  • the 7-methoxynaphthalene-2-sulfonyl chloride (3.80 g, 14.8 mmol) is also isolated as the major component from the above procedure as a white crystalline solid.
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • Boc-L-Asp-OBn (15 g, 46.4 mmol) is dissolved in 50 mL of THF and cooled to -10°C. The solution is treated with N-methylmorpholine (4.9 g, 48.7 mmol ) and stirred for 5 minutes. To the solution is added dropwise isobutyl chloroformate (6.3 g, 46.4 mmol). After the addition is completed, the solution is stirred for 1 minute, then filtered through a pad of Celite. The collected solution is cooled to -10°C. To the solution is added sodium borohydride (2.63 g, 70 mmol) predissolved in 50 mL of water. The solution is stirred for 2 minutes.
  • the solution is poured into a separatory funnel and diluted with 800 mL of EtOAc.
  • the organic layer is washed with water and saturated NaCl.
  • the organic layer is dried over MgSO 4 , filtered and concentrated.
  • the resulting residue is added to a solution of oxalyl chloride (30 mL of a 2 M solution in CH 2 CI 2 , 60 mmol), and methyl sulfoxide (7.25 g, 92.8 mmol) in 250 mL of CH 2 CI 2 at -78°C.
  • the reaction mixture is stirred at -78°C for 40 minutes, then triethylamine (14 g, 140 mmol) is added.
  • the reaction mixture is stirred at -78°C for 1 hour and then is stirred at room temperature for 30 minutes.
  • the solution is poured into 200 mL of a 20% citric acid/water solution.
  • the resulting mixture is poured into a separatory funnel and the layers are separated.
  • the organic layer is washed with water and saturated NaCl.
  • the organic layer is dried over MgSO 4 , filtered and concentrated.
  • the residue is purified by column chromatography eluting with a gradient of 10% EtOAc/hexanes to 30% EtOAc/hexanes.
  • the product aldehyde (12 g, 39 mmol) is obtained as an oil.
  • the title compound is prepared from 4-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using 7- methoxynaphthalene-2-sulfonyl chloride in place of 6-methoxynaphthalene-2- sulfonyi chloride.
  • the crude product is triturated from EtOAc to give the title compound as a white solid.
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using 6,7- dimethoxynaphthalene-2-sulfonyl chloride in place of 6-methoxynaphthalene- 2-sulfonyl chloride.
  • the crude product is purified by column chromatography in 50% EtOAc/CH 2 CI 2 to afford the title compound as a beige solid.
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • the crude residue is stirres in acetone to form a slurry an d the solid is filtered and dried.
  • the crude dissolved in 40 mL of 1 N NaOH solution and 95% EtOH ( ⁇ 100 mL) is added until a precipitate is formed and the solid is filtered and dried to give 1.49 g of the crude naphtho(2,3-d)-(1 ,3)dioxole-6-sulfonic acid, sodium salt.
  • the crude sulfonic acid, sodium salt (1.49 g, 5.27 mmol) is chlorinated in the presence of excess phosphorous oxychloride and phosphorous pentachloride as described in EXAMPLE 24, Part A to give the crude title compound. This product is of sufficient purity to be used in subsequent reactions.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using naphtho(2,3-d)-(1 ,3)dioxole-6-sulfonyl chloride in place of 6- methoxynaphthalene-2-sulfonyl chloride.
  • the crude product is triturated from CH 2 CI 2 to give the title compound as a beige solid.
  • Naphtho(2,3-d)-(1,3)dioxole-6-sulfonic acid [1-(3-cyanobenzyl)-2- oxopyrrolidin-3-(S)-yl]amide is converted to the title compound as described in EXAMPLE 24, Part C.
  • the imidate intermediate is formed over a period of 18 hours at room temperature.
  • the amidine formation occurs over a period of 18 hours at room temperature.
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • the residue is suspended in acetone and concentrated in vacuo two times and then is dried under high vacuum.
  • the solid is suspended in acetone, filtered and dried to yield the crude 7-benzyloxynaphthalene-2-sulfonic acid, sodium salt as a beige solid.
  • a mixture of the sulfonic acid, sodium salt (2.47 g) in 8 mL of thionyl chloride is heated at 80°C for 4 hours.
  • a drop of PMF is added with vigorous bubbling resulting and the mixture is heated for an additional 30 minutes.
  • the mixture is allowed to cool to room temperature and concentrated in vacuo.
  • the residue is diluted in EtOAc and washed successively with water (2x), saturated NaHCO 3 solution and saturated NaCl.
  • the organic layer is dried over anhydrous MgSO 4 , filtered and concentrated to yield the title compound as a beige solid (1.26 g, 3.78 mmol).
  • the crude product is of sufficient purity to be used in subsequent reactions.
  • Hydrogen sulfide gas is bubbled for 5 minutes through a solution of 7- benzyloxynaphthalene-2-sulfonic acid [1 -(3-cyanobenzyl)-2-oxopyrrolidin-3- (S)-yl]amide (0.32 g, 0.63 mmol) in 10 mL of a 10:1 mixture of
  • the resulting mixture is heated at reflux for 3 hours, allowed to cool to room temperature and stirred overnight.
  • the resulting mixture is concentrated in vacuo to provide the crude amidine salt.
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound (0.05 g, 0.08 mmol) as a white solid.
  • 6-benzyloxynaphthalene-2-sulfonic acid, sodium salt obtained is likewise chlorinated with excess thionyl chloride and 3 drops of DMF.
  • the crude product is triturated from 50% EtOAc/hexanes to give the title compound which is of sufficient purity to be used in subsequent reactions.
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1 % TFA) to 60% CH 3 CN/H 2 O (0.1 % TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • the title compound is prepared as described in EXAMPLE 25, Part A using 5- chloro-3-methylbenzo[b]thiophene-2-sulfonic acid [1-(3-cyanobenzyl)-2- oxopyrrolidin-3-(S)-yl]amide as the starting material.
  • the crude product is purified by column chromatography in a gradient of 2% EtOAc/CH 2 CI 2 to 10% EtOAc/CH 2 CI 2 to afford the title compound as a white solid.
  • a suspension of 2-methoxy-7-methylnaphthalene (5.30 g, 30.8 mmol) in 90 mL of 48% aqueous HBr is heated at reflux for a period of 2 hours.
  • the resulting mixture is allowed to cool to room temperature, diluted with water and partially neutralized with saturated NaHCO 3 solution.
  • the aqueous mixture is extracted with EtOAc twice and the combined organic layers are washed with water, saturated NaHCO 3 solution and saturated NaCl solution.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using 7- methylnaphthalene-2-sulfonyl chloride in place of 6-methoxynaphthalene-2- sulfonyl chloride.
  • the crude product is triturated from 50% EtOAc/ hexanes to give the title compound as a white solid.
  • the title compound is prepared as described in EXAMPLE 37, Part E using 2- methoxy-7-trifluoromethanesulfonylnaphthalene in place of 7-methyl-2- trifluoromethanesulfonylnaphthalene.
  • the crude product is purified by column chromatography in a gradient of 2% EtOAc/hexanes to 5% EtOAc/hexanes to afford the title compound as an oil.
  • reaction mixture is quenched with saturated NH 4 CI solution, diluted with EtOAc and the layers are separated.
  • the organic layer is washed with 1 N aqueous HCl, water, saturated NaHCO 3 solution and saturated NaCl solution.
  • the organic layer is dried over MgSO 4 , filtered and concentrated to provide crude product which is purified by column chromatography in a gradient of 2% EtOAc/hexanes to 5% EtOAc/hexanes to give a 3.5:1 mixture (0.56 g, 3.01 mmol) of the title compound as the major component and 2- methoxynaphthalene as the minor component.
  • EXAMPLE 37 Part C using the 3.5:1 mixture of 2-methoxy-7-ethylnaphthalene and 2-methoxynaphthalene in place of 2-methoxy-7-methylnaphthalene .
  • the crude demethylated product is partially purified by column chromatography in a gradient of 5% EtOAc/hexanes to 20% EtOAc/hexanes.
  • the 7-ethyl-2-naphthol mixture is converted to 7-ethyl-2-trifluoromethanesulfonylnaphthalene as described in EXAMPLE 37, Part A.
  • the crude triflated material is partially purified by column chromatography in a gradient of 2% EtOAc/hexanes to 5%
  • the 7-ethyl-2-trimethylstannylnaphthalene is converted to the title compound as described in EXAMPLE 37, Part F using 7-ethyl-2- trimethylstannylnaphthalene in place of 7-methyl-2- trimethylstannylnaphthalene and Et 2 O in place of THF.
  • the crude mixture is purified by column chromatography in a gradient of 5% EtOAc/hexanes to 10%
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylm ethyl) benzonitrile hydrochloride as in EXAMPLE 24, Part B using 7- ethylnaphthalene-2-sulfonyl chloride in place of 6-methoxynaphthalene-2- sulfonyl chloride.
  • the crude product is triturated from 50% EtOAc/hexanes to give the title compound as a white solid.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using N-Obz-5- chloro-6-aminonaphthalene-2-sulfonyl chloride in place of 6- methoxynaphthalene-2-sulfonyl chloride.
  • the crude product is purified by column chromatography using a gradient of 10% EtOAc/CH 2 CI 2 to 25%
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • N-Cbz-7-Aminonaphthalene-2-sulfonic acid, sodium salt is prepared as described in EXAMPLE 39, Part A using 7-aminonaphthalene-2-sulfonic acid, sodium salt (3 g, 12.2 mmol) in place of 6-aminonaphthalene-2-sulfonic acid, sodium salt.
  • a 60% dispersion of sodium hydride (0.21 g, 5.27 mmol) in mineral oil is washed with hexanes twice, suspended in 20 mL of DMF and the resulting suspension is cooled to 0°C.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using N-Cbz-7- methylaminonaphthalene-2-sulfonyl chloride in place of 6- methoxynaphthalene-2-sulfonyl chloride.
  • the crude product is purified by column chromatography using a gradient of 10% EtOAc/CH 2 CI 2 to 25%
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using 2- trifluoromethylacetamide-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride in place of 6-methoxynaphthalene-2-sulfonyl chloride.
  • the crude product is purified by column chromatography using a gradient of 10% EtOAc/CH 2 CI 2 to 25% EtOAc/CH 2 CI 2 to give the title compound as a solid.
  • the amidine formation occurred upon heating at reflux for 2 hours.
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • EXAMPLE 42 1 ,2,3,4-Tetrahydroisoquinoline-7-sulfonic acid ⁇ 1-[3- (aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-yl ⁇ methyl amide
  • the title compound is prepared as described in EXAMPLE 41, Part C using 2-trifluoromethylacetamide-1,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]methyl amide as the starting material.
  • the crude product is triturated from 50% EtOAc/CH 2 CI 2 to afford the title compound as a solid.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using 7- methoxynaphthalene-2-sulfonyl chloride in place of 6-methoxynaphthalene-2- sulfonyi chloride.
  • the crude product is triturated from EtOAc to give the title compound as a white solid.
  • the title compound is prepared as described in EXAMPLE 25, Part A using 7- methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)- yl]amide as the starting material and p-nitrobenzyl bromide in place of methyl iodide.
  • the crude product is purified by column chromatography in 50%
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound (0.11 g, 0.14 mmol) as a white solid.
  • the title compound is prepared as described in EXAMPLE 25, Part A using 7- methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3 -(S)- yl]amide as the starting material and m-nitrobenzyl bromide in piace of methyl iodide.
  • the crude product is purified by column chromatography in 10% EtOAc/CH 2 CI 2 to afford the title compound as a solid.
  • the title compound is prepared as described in EXAMPLE 25, Part A using 7- methoxynaphthalene-2-sulfonic acid [1 -(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)- yl]amide as the starting material and o-nitrobenzyl bromide in place of methyl iodide.
  • the crude product is triturated from 50% EtOAc/hexanes to afford the title compound as a solid.
  • EXAMPLE 48 7-Methoxynaphthalene-2-sulfonic acid ⁇ 1-[3-(aminoiminomethyl)benzyl]-2- oxopyrrolidin-3-(S)-yl ⁇ -(2-aminobenzyl)amide bistrifluoroacetate.
  • the title compound is prepared from 3- (3-(S)-amino -2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using trans- ⁇ - styrenesulfonyl chloride in place of 6-methoxynaphthalene-2-sulfonyl chloride.
  • the crude product is triturated from 50% EtOAc/hexanes to give the title compound as a solid.
  • 2-Phenylethenesulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3(S)-yl]amide is converted to the title compound as described in EXAMPLE 24, Part C.
  • the imidate intermediate is formed over a period of 18 hours at room temperature.
  • the amidine formation occurred over a period of 18 hours at room temperature.
  • the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 80% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using 2- chloroethanesulfonyl chloride in place of 6-methoxynaphthalene-2-sulfonyl chloride.
  • the crude product is purified by column chromatography in a gradient of 10% EtOAc/CH 2 CI 2 to 40% EtOAc/CH 2 CI 2 to afford the title compound as a solid.
  • the crude product is purified by RP-HPLC eluting in a gradient of 2% CH 3 CN/H 2 O (0.1% TFA) to 50% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • n-butyl lithium (2 mL of a 1.6 M solution in hexanes, 3.2 mmol). After 30 minutes, the solution is transferred to a flask containing 10 mL of SO 2 in 40 mL of Et 2 O at -78°C. The solution is stirred at - 78°C for 30 minutes, and then at ambient temperature for 2 hours. After this time, the solution is concentrated. The residue is dissolved in 20 mL of hexanes.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using 2'- methoxybiphenyl-4-sulfonyl chloride in place of 6-methoxynaphthalene -2- sulfonyl chloride.
  • the crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/CH 2 CI 2 to 20% EtOAc/CH 2 CI 2 to give the title compound as a white foam.
  • the crude product is purified by RP-HPLC eluting with a gradient of 10% CH 3 CN/H 2 O (0.1% TFA) to 60% CH 3 CN/H 2 O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
  • the title compound is prepared as described in EXAMPLE 54, Part A using isoquinoline-5-sulfonic acid in place of 5,6,7,8-tetrahydrophenanthrene-3- sulfonic acid, sodium salt.
  • the crude product is purified by triturating with Et 2 O to give the product as a white solid.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B, substituting isoquinoline-5-sulfonyl chloride for 6-methoxynaphthalene-2-sulfonyl chloride.
  • the crude product is purified by column chromatography eluting with a gradient of 2% MeOH/CH 2 CI 2 to 4% MeOH/CH 2 CI 2 to give the title compound as a white foam.
  • the title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1- ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B, substituing 5- chlorothiophene-2-sulfonyl chloride for 6-methoxynaphthalene-2-sulfor ⁇ yl chloride.
  • the crude product is used without further purification.
  • the title compound is prepared as described in EXAMPLE 25, Part A using 7- methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)- yl]amide, prepared as described in EXAMPLE 43, Part A, and ethyl iodide.
  • the crude product is purified by column chromatography eluting with gradient of 15% EtOAc/CH 2 CI 2 to 25% EtOAc/CH 2 CI 2 to afford the title compound as a white foam.
  • EXAMPLE 59 7-Methoxy-2-napthalenesulfonic acid ⁇ 1-[3-(aminoiminomethyl)benzyl]-2-oxo- 3(S)-pyrrolidin-3-yl ⁇ (3-fluorobenzyl)amide trifluoroacetate.
  • the title compound is prepared as described in EXAMPLE 25, Part A using 7- methoxynaphthalene-2-sulfonic acid [1 -(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)- yl]amide, prepared as described in EXAMPLE 43, part A, and 3-fluorobenzyl bromide.
  • the crude product is purified by column chromatography eluting with gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to afford the title compound as a white foam.
  • the title compound is prepared as described in EXAMPLE 25, Part A using 7- methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)- yl]amide, prepared as described in EXAMPLE 43. part A, and 4-metnylbenzyl bromide.
  • the crude product is purified by column chromatography eluting with gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to afford the title compound as a white foam.
  • the title compound is prepared as described in EXAMPLE 25, Part A using 7- methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)- yl]amide, prepared as described in EXAMPLE 43, Part A, and 3-methylbenzyl bromide.
  • the crude product is purified by column chromatography eluting with gradient of 40% EtOAc/hexanes to 50% EtOAc/ hexanes to afford the title compound as a white foam.
  • the title compound is prepared as described in EXAMPLE 25, Part A using 7-methoxynaphthalene-2-sulfonic acid [1 -(3-cyanobenzyl)-2-oxopyrrolidin-3- (S)-yl]amide, prepared as described in EXAMPLE 43, part A, and 2-bromo- methylnaphthalene.
  • the crude product is purified by column chromatography eluting with gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to afford the title compound as a white foam.
  • the title compound is prepared as described in EXAMPLE 25, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3- (S)-yl]amide, prepared as described in EXAMPLE 43, part A, and cinnamyl bromide.
  • the crude product is purified by column chromatography eluting with gradient of 20% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound as a white foam.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyrrole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP96919298A 1995-06-07 1996-06-07 Substituierte ((sulfinsäure, sulfonsäure, sulfonylamino oder sulfinylamino)n-(aminoimonomethyl)phenylalkyl)-azaheterocyclylamid-derivate Expired - Lifetime EP0853618B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US481024 1995-06-07
US08/481,024 US5612353A (en) 1995-06-07 1995-06-07 Substituted (sulfinic acid, sulfonic acid, sulfonylamino or sulfinylamino) N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide compounds
PCT/US1996/009816 WO1996040679A1 (en) 1995-06-07 1996-06-07 Substituted (sulfinic acid, sulfonic acid, sulfonylamino or sulfinylamino) n-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide compounds

Publications (3)

Publication Number Publication Date
EP0853618A1 true EP0853618A1 (de) 1998-07-22
EP0853618A4 EP0853618A4 (de) 2000-03-15
EP0853618B1 EP0853618B1 (de) 2011-08-17

Family

ID=23910281

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96919298A Expired - Lifetime EP0853618B1 (de) 1995-06-07 1996-06-07 Substituierte ((sulfinsäure, sulfonsäure, sulfonylamino oder sulfinylamino)n-(aminoimonomethyl)phenylalkyl)-azaheterocyclylamid-derivate

Country Status (21)

Country Link
US (1) US5612353A (de)
EP (1) EP0853618B1 (de)
JP (1) JP4312829B2 (de)
KR (1) KR100291711B1 (de)
CN (1) CN1190395A (de)
AP (1) AP799A (de)
AT (1) ATE520655T1 (de)
AU (1) AU714319B2 (de)
BG (1) BG63628B1 (de)
BR (1) BR9608405A (de)
CA (1) CA2223403C (de)
CZ (1) CZ385397A3 (de)
EA (1) EA000700B1 (de)
HU (1) HUP9801882A3 (de)
MX (1) MX9709977A (de)
NO (1) NO310457B1 (de)
OA (1) OA10752A (de)
PL (1) PL323780A1 (de)
SI (1) SI9620093A (de)
SK (1) SK160697A3 (de)
WO (1) WO1996040679A1 (de)

Families Citing this family (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5731315A (en) * 1995-06-07 1998-03-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted sulfonic acid n- (aminoiminomethyl)phenylalkyl!-azaheterocyclamide compounds
US5958918A (en) * 1995-06-07 1999-09-28 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted (sulfinic acid, sulfonic acid, sulfonylamino or sulfinylamino) N- (aminominomethyl)phenylalkyl!-azaheterocyclylamide compounds
US6034093A (en) * 1995-06-07 2000-03-07 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide compounds
US6080767A (en) * 1996-01-02 2000-06-27 Aventis Pharmaceuticals Products Inc. Substituted n-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides
US6057342A (en) * 1996-08-16 2000-05-02 Dupont Pharmaceutical Co. Amidinophenyl-pyrrolidines, -pyrrolines, and -isoxazolidines and derivatives thereof
ES2184145T3 (es) * 1996-12-13 2003-04-01 Aventis Pharma Inc Compuestos de acido sulfonico o sulfonilamino-n-(heteroaralquil)-azaheterociclilamida.
US6602864B1 (en) * 1996-12-13 2003-08-05 Aventis Pharma Deutschland Gmbh Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclylamide compounds
DE69835430T2 (de) 1997-05-30 2007-03-08 Takeda Pharmaceutical Co. Ltd. Sulfonamidderivate, ihre herstellung und verwendung
ZA985247B (en) * 1997-06-19 1999-12-17 Du Pont Merck Pharma Guanidine mimics as factor Xa inhibitors.
DE69833036T2 (de) 1997-09-30 2006-06-22 Daiichi Pharmaceutical Co., Ltd. Sulfonylderivate
US6271237B1 (en) 1997-12-22 2001-08-07 Dupont Pharmaceuticals Company Nitrogen containing heteromatics with ortho-substituted P1s as factor Xa inhabitors
IL136637A0 (en) * 1997-12-22 2001-06-14 Du Pont Pharm Co Nitrogen containing heteroaromatics with ortho-substituted pi's as factor xa inhibitors
IL137517A0 (en) * 1998-01-27 2001-07-24 Aventis Pharm Prod Inc Substituted oxoazaheterocyclyl factor xa inhibitors
CA2317017A1 (en) 1998-02-05 1999-08-12 Takeda Chemical Industries, Ltd. Sulfonamide derivatives, their production and use
US6291514B1 (en) 1998-02-09 2001-09-18 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors
NZ506507A (en) * 1998-02-09 2003-08-29 Dimensional Pharm Inc Heteroaryl amidine, methylamidine or guanidine derivatives useful as urokinase inhibitors
CA2340100A1 (en) * 1998-08-11 2000-02-24 Daiichi Pharmaceutical Co., Ltd. Novel sulfonyl derivatives
DE19839499A1 (de) * 1998-08-29 2000-03-02 Merck Patent Gmbh 2-Oxo-2H-chinolinderivate
JP2003529531A (ja) * 1998-11-25 2003-10-07 アヴェンティス ファーマシューティカルズ インコーポレイテッド 置換オキソアザへテロシクリルＸａ因子阻害剤
BR9917036A (pt) * 1999-02-09 2002-07-30 Dimensional Pharm Inc Amidinas heteroarila, metilamidinas e guanidinas como inibidores de protease
DE19909237A1 (de) * 1999-03-03 2000-09-07 Merck Patent Gmbh Pyrazol-3-on-derivate
US6794412B1 (en) * 1999-03-11 2004-09-21 Bristol-Myers Squibb Pharma Company Treatment of thrombosis by combined use of a factor Xa inhibitor and aspirin
JP2001026506A (ja) * 1999-04-28 2001-01-30 Takeda Chem Ind Ltd スルホンアミド誘導体
US6586617B1 (en) * 1999-04-28 2003-07-01 Sumitomo Chemical Takeda Agro Company, Limited Sulfonamide derivatives
CA2383492A1 (en) 1999-06-22 2000-12-28 Takeda Chemical Industries, Ltd. Acylhydrazine derivatives, their production and use
DE60041584D1 (de) * 1999-07-28 2009-04-02 Aventis Pharma Inc Substituierte oxoazaheterozyclische verbindungen
US6544981B2 (en) * 2000-06-09 2003-04-08 Bristol-Myers Squibb Company Lactam inhibitors of factor Xa and method
US6511973B2 (en) 2000-08-02 2003-01-28 Bristol-Myers Squibb Co. Lactam inhibitors of FXa and method
US6838479B2 (en) 2000-09-11 2005-01-04 Genentech, Inc. Amidine inhibitors of serine proteases
CA2428123A1 (en) * 2000-11-08 2002-05-16 Shuji Kitamura Carbamate derivatives, their production and use
US6982251B2 (en) 2000-12-20 2006-01-03 Schering Corporation Substituted 2-azetidinones useful as hypocholesterolemic agents
AR032230A1 (es) * 2001-01-16 2003-10-29 Sumitomo Chem Takeda Agro Co Derivado sulfonamida conteniendo una composicion agricola y horticola
US20060287254A1 (en) * 2001-01-26 2006-12-21 Schering Corporation Use of substituted azetidinone compounds for the treatment of sitosterolemia
TWI337083B (en) * 2001-01-26 2011-02-11 Schering Corp Combinations of peroxisome proliferator-activated receptor (ppar) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications
JP2004518688A (ja) 2001-01-30 2004-06-24 ブリストル−マイヤーズ　スクイブ　カンパニー ファクターＸａ阻害剤のスルホンアミドラクタムおよびその方法
US6710061B2 (en) 2001-03-09 2004-03-23 Ortho-Mcneil Pharamceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
JP2004520438A (ja) 2001-03-09 2004-07-08 オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド セリンプロテアーゼインヒビターとしてのアミノピロリジンスルホンアミド
DE10112768A1 (de) * 2001-03-16 2002-09-19 Merck Patent Gmbh Phenylderivate 3
DE10139060A1 (de) 2001-08-08 2003-02-20 Merck Patent Gmbh Phenylderivate
US7053080B2 (en) * 2001-09-21 2006-05-30 Schering Corporation Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors
ATE345793T1 (de) * 2001-09-21 2006-12-15 Schering Corp Behandlung von xanthom mittels azetidinon- derivate als hemmer der sterol absorption
DE10239821A1 (de) 2002-08-29 2004-03-11 Roche Diagnostics Gmbh Verbesserung der Spezifität bei der Bestimmung von Antithrombin
WO2004048363A1 (ja) 2002-11-22 2004-06-10 Takeda Pharmaceutical Company Limited イミダゾール誘導体、その製造法および用途
DK1569912T3 (en) 2002-12-03 2015-06-29 Pharmacyclics Inc 2- (2-hydroxybiphenyl-3-yl) -1h-benzoimidazole-5-carboxamidine derivatives as factor VIIa inhibitors.
DE10302500A1 (de) 2003-01-23 2004-07-29 Merck Patent Gmbh Carbonsäureamidderivate
ES2318274T3 (es) * 2003-03-07 2009-05-01 Schering Corporation Compuestos de azetidinona sustituida, formulaciones y uso de los mismos para el tratamiento de hipercolesterolemia.
ATE406364T1 (de) * 2003-03-07 2008-09-15 Schering Corp Substituierte azetidinon-derivate, deren pharmazeutische formulierungen und deren verwendung zur behandlung von hypercholesterolemia
US7459442B2 (en) * 2003-03-07 2008-12-02 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
AU2004249671A1 (en) 2003-05-20 2004-12-29 Genentech, Inc. Benzofuran inhibitors of factor VIIa
JP2007505160A (ja) 2003-05-20 2007-03-08 ジェネンテック・インコーポレーテッド 第ＶＩＩａ因子のアシルスルファミド阻害剤
NZ547528A (en) * 2003-10-29 2008-11-28 Elan Pharm Inc N-substituted benzene sulfonamides
EP1533298A1 (de) 2003-11-21 2005-05-25 Newron Pharmaceuticals S.p.A. 3-aminopyrrolidonederivate
TWI396686B (zh) 2004-05-21 2013-05-21 Takeda Pharmaceutical 環狀醯胺衍生物、以及其製品和用法
JP5208510B2 (ja) * 2004-11-23 2013-06-12 アストラゼネカ・アクチエボラーグ 呼吸器疾患の処置に有用なフェノキシ酢酸誘導体
CA2607670A1 (en) * 2005-05-10 2006-11-16 Vertex Pharmaceuticals Incorporated Bicyclic derivatives as modulators of ion channels
WO2020113094A1 (en) 2018-11-30 2020-06-04 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993001208A1 (de) * 1991-07-03 1993-01-21 Basf Aktiengesellschaft 2-[3-(4-amidino-phenyl)]-propionsäurederivate, ihre herstellung und verwendung
WO1993007141A1 (en) * 1991-10-11 1993-04-15 Smithkline Beecham Corporation Heterocyclic 3-phenylpyrrolidin-2-ones, their preparation and use for the manufacture of a medicament for inhibiting tumor necrosis factor production
JPH05201971A (ja) * 1992-01-28 1993-08-10 Hokuriku Seiyaku Co Ltd 環状アミン含有ベンゼンスルホンアミド誘導体
WO1995008533A1 (fr) * 1993-09-21 1995-03-30 Yamanouchi Pharmaceutical Co., Ltd. Derive de n-(3-pyrrolidinyl)benzamide
WO1995008534A1 (en) * 1993-09-20 1995-03-30 Glaxo Wellcome Inc. 3-(3,4-dioxyphenyl)-pyrrolidines as type iv phosphodiesterase inhibitors for the treatment of inflammatory diseases
WO1995018105A1 (fr) * 1993-12-24 1995-07-06 Sanofi Derives de 1,3-dihydroindol-2-one substitues en 3 par un groupe azote comme agonistes et/ou antagonistes de la vasopressine et/ou de l'ocytocine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993001208A1 (de) * 1991-07-03 1993-01-21 Basf Aktiengesellschaft 2-[3-(4-amidino-phenyl)]-propionsäurederivate, ihre herstellung und verwendung
WO1993007141A1 (en) * 1991-10-11 1993-04-15 Smithkline Beecham Corporation Heterocyclic 3-phenylpyrrolidin-2-ones, their preparation and use for the manufacture of a medicament for inhibiting tumor necrosis factor production
JPH05201971A (ja) * 1992-01-28 1993-08-10 Hokuriku Seiyaku Co Ltd 環状アミン含有ベンゼンスルホンアミド誘導体
WO1995008534A1 (en) * 1993-09-20 1995-03-30 Glaxo Wellcome Inc. 3-(3,4-dioxyphenyl)-pyrrolidines as type iv phosphodiesterase inhibitors for the treatment of inflammatory diseases
WO1995008533A1 (fr) * 1993-09-21 1995-03-30 Yamanouchi Pharmaceutical Co., Ltd. Derive de n-(3-pyrrolidinyl)benzamide
WO1995018105A1 (fr) * 1993-12-24 1995-07-06 Sanofi Derives de 1,3-dihydroindol-2-one substitues en 3 par un groupe azote comme agonistes et/ou antagonistes de la vasopressine et/ou de l'ocytocine

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
BEN-ISHAI D. ET AL.: "Intra vs intermolecular amidoalkylation of aromatics" TETRAHEDRON, vol. 43, no. 2, 1987, pages 439-450, XP002126456 *
BEN-ISHAI D.: "Intramolecular amidoalkylation of olefins" JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL COMMUNICATIONS, no. 15, 1980, pages 687-688, XP002126453 *
BUCSH R.A. ET AL.: "Synthesis and antimicrobial evaluation of a series of 7-[3-amino-(or aminomethyl)-4-aryl (or cyclopropyl)-1-pyrrolidinyl]-4-quinolone- and -1,8-naphthyridone-3-carboxylic acids" JOURNAL OF MEDICINAL CHEMISTRY, vol. 36, no. 26, 1993, pages 4139-4151, XP002126457 *
GRAY C.J. ET AL.: "Preparation and properties of some citrulline p-nitroanilide derivatives for possible use as protease substrates" TETRAHEDRON, vol. 38, no. 10, 1982, pages 1465-1470, XP002126454 *
KAMBER M. & JUST G.: ".gamma.-Phosphono-.gamma.-lactones. The use of allyl esters as easily removable phosponate protecting groups" CANADIAN JOURNAL OF CHEMISTRY, vol. 63, 1985, pages 823-827, XP002126444 *
PATENT ABSTRACTS OF JAPAN vol. 17, no. 644 (C-1134), 30 November 1993 (1993-11-30) & JP 05 201971 A (HOKURIKU SEIYAKU CO. LTD.), 10 August 1993 (1993-08-10) *
RANGANATHAN S. ET AL.: "Spontaneous cyclization of a chain shortened lysine analog" TETRAHEDRON LETTERS, vol. 29, no. 25, 1988, pages 3111-3114, XP002126448 *
ROWLEY M. ET AL.: "Routes to 4-substituted analogues of the glycine/NMDA antagonist HA-966. Enantioselective synthesis of (3R,4R) 3-amino-1-hydroxy-4-methyl-2-pyrrolidinone (L-687,414)" TETRAHEDRON, vol. 48, no. 17, 1992, pages 3557-3570, XP002126450 *
See also references of WO9640679A1 *
SKILES J.W. ET AL.: "Elastase inhibitors containing conformationally restricted lactams as P3-P2 dipeptide replacements" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 3, no. 4, 1993, pages 773-778, XP000673137 *
SMITH A.B. ET AL.: "De novo design, synthesis, and X-ray crystal structures of pyrrolinone-based .beta.-strand peptidomimetics" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 116, no. 22, 1994, pages 9947-9962, XP002126451 *
SONDHEIMER E. & HOLLEY R.W.: "Imides from asparagine and glutamine" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 76, 5 May 1954 (1954-05-05), pages 2467-2470, XP002126452 *
THAISRIVONGS S. ET AL.: "Conformationally constrained renin inhibitory peptides: .gamma.-Lactam-bridged dipeptide isostere as conformational restriction" JOURNAL OF MEDICINAL CHEMISTRY, vol. 31, no. 7, July 1988 (1988-07), pages 1369-1376, XP002126446 *
THORSETT E.D. ET AL.: "Conformationally restricted inhibitors of angiotensin converting enzyme: Synthesis and computations" JOURNAL OF MEDICINAL CHEMISTRY, vol. 29, no. 2, February 1986 (1986-02), pages 251-260, XP002126455 *
WOLF J.-P. & RAPOPORT H.: "Conformationally constrained peptides. Chirospecific synthesis of-4-alkyl-substituted .gamma.-lactam-bridged dipeptides from L-aspartic acid" JOURNAL OF ORGANIC CHEMISTRY, vol. 54, no. 13, 23 June 1989 (1989-06-23), pages 3164-3173, XP002126447 *
ZYDOWSKY T.M. ET AL.: "Efficient and versatile synthesis of dipeptide isosteres containing .gamma.- or .delta.-lactams" JOURNAL OF ORGANIC CHEMISTRY, vol. 53, no. 24, 25 November 1988 (1988-11-25), pages 5607-5616, XP002126445 *

Also Published As

Publication number Publication date
KR19990022386A (ko) 1999-03-25
NO975762D0 (no) 1997-12-08
HUP9801882A3 (en) 1999-01-28
CZ385397A3 (cs) 1999-05-12
NO310457B1 (no) 2001-07-09
KR100291711B1 (ko) 2001-09-17
NO975762L (no) 1998-02-06
SK160697A3 (en) 1998-11-04
EA199800043A1 (ru) 1998-08-27
JP4312829B2 (ja) 2009-08-12
BG102162A (en) 1998-09-30
CA2223403A1 (en) 1996-12-19
CN1190395A (zh) 1998-08-12
AU6166996A (en) 1996-12-30
AU714319B2 (en) 2000-01-06
PL323780A1 (en) 1998-04-27
MX9709977A (es) 1998-07-31
HUP9801882A2 (hu) 1998-12-28
AP799A (en) 2000-01-19
SI9620093A (sl) 1999-02-28
WO1996040679A1 (en) 1996-12-19
US5612353A (en) 1997-03-18
EP0853618B1 (de) 2011-08-17
OA10752A (en) 2001-07-04
EA000700B1 (ru) 2000-02-28
JPH11507368A (ja) 1999-06-29
AP9701144A0 (en) 1998-01-31
BR9608405A (pt) 1999-08-24
BG63628B1 (bg) 2002-07-31
ATE520655T1 (de) 2011-09-15
EP0853618A4 (de) 2000-03-15
CA2223403C (en) 2002-04-23

Similar Documents

Publication Publication Date Title
EP0853618A1 (de) Substituierte ((sulfinsäure, sulfonsäure, sulfonylamino oder sulfinylamino)n-(aminoimonomethyl)phenylalkyl)-azaheterocyclylamid-derivate
US5731315A (en) Substituted sulfonic acid n- (aminoiminomethyl)phenylalkyl!-azaheterocyclamide compounds
EP1051176B1 (de) SUBSTITUIERTE OXOAZAHETEROCYCLYL FAKTOR Xa HEMMER
KR100348338B1 (ko) 치환된n-[(아미노이미노메틸또는아미노메틸)페닐]프로필아미드및이를포함하는약제학적조성물
US6034093A (en) Substituted sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide compounds
WO2001039759A2 (en) Sulfonic acid or sulfonylamino n-(heteroaralkyl)-azaheterocyclylamide compounds
HRP20020076A2 (en) Substituted oxoazaheterocyclyl compounds
AU726637B2 (en) Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclylamide compounds
EP1086099B1 (de) Sulfonsäure- oder sulfonylamino-n-(heteroaralkyl)-azaheterozyklylamidverbindungen
WO2000032590A1 (en) SUBSTITUTED OXOAZAHETEROCYCLYL FACTOR Xa INHIBITORS
US5958918A (en) Substituted (sulfinic acid, sulfonic acid, sulfonylamino or sulfinylamino) N- (aminominomethyl)phenylalkyl!-azaheterocyclylamide compounds
CZ20002728A3 (cs) Substituované oxoazaheterocyklylové inhibitory faktoru Xa, způsob jejich přípravy a farmaceutický prostředek, který je obsahuje

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19971217

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: LV PAYMENT 971217;SI PAYMENT 971217

RIC1 Information provided on ipc code assigned before grant

Free format text: 7C 07D 207/26 A, 7A 61K 31/40 B, 7C 07D 407/12 B, 7C 07D 401/12 B, 7A 61K 31/47 B, 7C 07D 409/14 B, 7A 61K 31/44 B, 7C 07D 207/14 B, 7C 07D 207/40 B, 7C 07D 211/76 B, 7A 61K 31/445 B, 7C 07D 223/12 B, 7A 61K 31/55 B, 7C 07D 409/12 B, 7C 07D 403/12 B, 7A 61K 31/505 B, 7C 07D 205/085 B, 7A 61K 31/395 B, 7A 61K 31/415 B, 7C 07D 401/06 B, 7C 07D 409/06 B, 7C 07D 407/06 B

A4 Supplementary search report drawn up and despatched

Effective date: 20000127

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: AVENTIS PHARMACEUTICALS PRODUCTS INC.

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: AVENTIS PHARMACEUTICALS INC.

17Q First examination report despatched

Effective date: 20040406

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: AVENTIS PHARMACEUTICALS, INC.

RTI1 Title (correction)

Free format text: SUBSTITUTED (SULFINIC ACID, SULFONIC ACID, SULFONYLAMINO OR SULFINYLAMINO) N- (AMINOIMINOMETHYL)PHENYLALKYL -AZAHETEROCYCLYLAMIDE COMPOUNDS

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAC Information related to communication of intention to grant a patent modified

Free format text: ORIGINAL CODE: EPIDOSCIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Extension state: LV SI

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 69638409

Country of ref document: DE

Effective date: 20111020

REG Reference to a national code

Ref country code: NL

Ref legal event code: VDEP

Effective date: 20110817

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20111219

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110817

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110817

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110817

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 520655

Country of ref document: AT

Kind code of ref document: T

Effective date: 20110817

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110817

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20111118

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110817

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110817

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110817

26N No opposition filed

Effective date: 20120521

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 69638409

Country of ref document: DE

Effective date: 20120521

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120630

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20120607

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20130228

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 69638409

Country of ref document: DE

Effective date: 20130101

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120630

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120702

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130101

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120607

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20111128

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120630

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120607

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120607